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Adrenergic agonists
Sympathomimetics drugs
Pharmacology I/ Lecture 5
Dr. Hiwa K. Saaed, HD, M.Sc, Ph.D

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agents that act on pathways mediated by
the endogenous catecholamines (CAO);
1. norepinephrine
2. epinephrine.
NEP & EP are modulate the
 Rate and force of contraction of heart.
 Resistance (constriction and dilation) of blood
vessels and bronchioles.
 Release of insulin,
 breakdown of fat (lipolysis).
Adrenergic agonists

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synthesis,
storage,
release,
binding
removal (reuptake) of
the neurotransmitter
They are frontline
therapies for
hypertension,
depression, shock,
asthma, angina & etc.
drugs target:

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 Tyrosine hydroxylase can be inhibited by methyl-p-
tyrosine.
 MAO: inhibitors of MAO (e.g., phenelzine,
tranylcypromine)
 The mobile pool; many indirect-acting
sympathomimetics (e.g., amphetamine, ephedrine,
tyramine) can displace NE from the mobile pool
 Uptake: some indirect-acting sympathomimetics
(cocaine, TCA).
Drug Targets

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 Prejunctional α-receptors: (e.g., clonidine, alpha
methyldopa) cause inhibition of NE release.
 Granular uptake of NE: blocker of granular uptake
of NE (e.g., reserpine) .
 NE release from granules: blockers (e.g.,
guanethidine).
 Postjunctional receptors: postjunctional receptors
can be activated or blocked.
Drug Targets

6. Classification
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divided into subgroups
on the basis of their
 Spectrum of action:
 α, β, or dopamine
receptor affinity
 Mode of action:
 direct, indirect or
both

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Adrenergic agonists
 Direct acting:
I. α agonists:
• Non selective,
• α1-selective,
• α2-selective
II. β agonists:
• Non selective,
• β1-selective,
• Β2-selective

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 Indirect acting ↑ CAO in the synapse:
1. Releaser: Amphetamine, tyramine
Potentiate by MAOI, COMT blocker. Why?
2. Reuptake inhibitor: Cocaine, TCA
 Mixed: Ephedrine, metaraminol
Adrenergic agonists

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Removal of NE may:
 Diffuse out and enter the general circulation.
 Be metabolized by COMT in the synaptic
 Be recaptured by an uptake systems into the
neuron

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Adrenoceptors
 Selective for NE & EP.
 dopamine can also activate some adrenoceptors at
very high ‘supraphysiologic’ concentrations.
 Divided into two main classes:
 α & β adrenoceptors
 All are members of GPCR superfamily.

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α-receptors:
EP≥NE>>Isoproterenol

12. β-receptors:
Isop>EP>NE
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 based on their affinities for a agonists and blocking
drugs, α-receptors are subdivided into two subgroups
α1 & α2,
e.g., α1 receptors have a higher affinity for
phenylephrine than do α2 receptors.
 Conversely, clonidine selectively binds to α2
receptors and has less effect on α1 receptors.
α-adrenoceptors (α1 & α2)

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α-receptors:
 α1 Are present on the postsynaptic membrane
 α2 Located primarily on presynaptic nerve endings.
The stimulation of α2 receptors causes feedback
inhibition of the ongoing release of NE;
 α2 Located on other cells such as the β-cell of the
pancreas control insulin output.

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β-receptors:
 Subdivided to β1, β2 and β3-receptors
 β1-receptors have ~equal affinities for both EP &
NE.,
 β2-receptors have higher affinity for EP than for
NE.
 thus tissue with a predominance of β2-receptors
(vasculature of skeletal muscle) are particularly
responsive to hormonal effects of circulating EP
released by adrenal medulla.

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β-receptors
Mechanism of action:
 binding of neurotransmitter at the β1 or β2-receptor→
result in activation of AC→↑cAMP concentrations
within the cell.

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Mechanisms of action of adrenergic receptors :

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Desensitization of receptors:
 Prolonged exposure to the CAO reduces the
responsiveness of the receptors due to:
1. Sequestration of the receptors
2. Downregulation (destruction, or decreased
synthesis)
3. An inability to couple to G-protein

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A. Catecholamine properties:
 High potency in activating α & β receptors
 Rapid inactivation by:
1. COMT postsynaptically, gut wall,
2. MAO intraneuronally, liver or gut
Thus,
CAO have only a brief duration of action when given
parenterally, and are ineffective when administered
orally because of inactivation.
 Poor penetration into the CNS (polar)

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B. Non Catecholamine properties :
 phenylephrine, ephedrine, amphetamine
 Have longer t1/2 because they are not inactivated by
COMT, and they are poor substrate for MAO
 Increased lipid solubility permits the greater access to
the CNS

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Major effects mediated by adrenoceptors

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SITE OF ACTION

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SITE OF ACTION